Mechanisms and translation of lipid resuscitation

脂质复苏的机制和转化

• 批准号: 8333735
• 负责人: Israel Rubinstein
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333735
• 关键词: Accounting; Acute; Admission activity; Adrenergic beta-Antagonists; Aging; Alcohols; American; American Heart Association; Animal Model; Animals; Antidotes; Award; Binding; Blood capillaries; Blood flow; Brain; Bupivacaine; Bypass; Calcium Channel Blockers; Cardiac; Cardiopulmonary Resuscitation; Cardiotoxicity; Cardiovascular Physiology; Case Study; Cells; Cessation of life; Cocaine; Conduction Anesthesia; Cyclodextrins; Data Set; Development; Diffusion; Drug Prescriptions; Drug abuse; Drug toxicity; Elderly; Electron Microscopy; Emulsions; Endothelium; Fatty acid glycerol esters; Funding; Generic Drugs; Goals; Great Britain; Guidelines; Gunshot wound; Health; Heart; Histologic; Indium; Information Systems; Infusion procedures; Inpatients; Instruction; Intoxication; Intravenous Fat Emulsions; Ireland; Ischemia; Life; Lipids; Liposomes; Local Anesthetics; Measures; Medical; Metabolic; Military Personnel; Modification; Morbidity - disease rate; Myocardial; Neurologic; Neurologic Manifestations; Normal tissue morphology; Organ; Outcome; Overdose; Pharmaceutical Preparations; Phase; Physicians; Plasma; Play; Poisoning; Population; Prevalence; Process; Publishing; Radiolabeled; Rattus; Reaction Time; Recovery; Reperfusion Therapy; Resistance; Resuscitation; Risk; Signal Transduction; Site; Societies; Symptoms; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Toxin; Translating; Translations; Treatment Protocols; Tricyclic Antidepressive Agents; United States; Veterans; Work; aqueous; base; capillary; clinical practice; cocaethylene; cocaine overdose; cocaine use; effective therapy; fatty acid metabolism; improved; in vivo; inhibitor/antagonist; light microscopy; migration; nanomedicine; novel; novel strategies; particle; patient safety; prevent; radiotracer; research study; soy; uptake; vehicular accident

DESCRIPTION (provided by applicant): Work funded under the PI's previous VA Merit award has contributed directly to a novel and now widely accepted life-saving treatment for local anesthetic systemic toxicity (LAST). Intravenous lipid emulsion (ILE) resuscitation has also been used in many instances to rapidly reverse acute cardiac and neurological symptoms of toxicity caused by a wide range of lipophilic (fat soluble) medications. In many published case reports involving LAST or other overdoses, ILE was effective even after standard resuscitation measures had failed. ILE is now a principle element in treatment guidelines published by the American Society of Regional Anesthesia, the Anaesthetists of Great Britain and Ireland, the Resuscitation Council (UK) and was added to the most recent American Heart Association ACLS guidelines for treating LAST. Drug overdose is the second leading cause of accidental death in the United States contributing to 36,000 fatalities in 2007 placing it ahead of gunshot wounds and just behind motor vehicle accidents. Moreover, veterans are at particular risk given the prevalence of both illicit drug abuse and the difficulty for a geriatric population to adhere to instructions for such prescription drugs as long acting calcium channel blockers that can be potentially fatal in overdose. Notably, ILE has been used effectively in treating overdose of many common prescription medications (e.g. beta blockers, tricyclic antidepressants or calcium channel blockers) that can be highly resistant to standard resuscitation measures. Identifying the precise mechanism(s) underlying ILE holds the promise of improving its efficacy and providing an effective, generic antidotal treatment for a range of life-threatening toxic drug overdoses. However, the precise mechanisms of ILE are not well understood. The conventional explanation involves partitioning of the offending toxin into the newly created lipemic plasma phase, or 'lipid sink'. However, even this mechanism has not been tested rigorously in vivo. Moreover, we have observed that key aspects of ILE cannot be explained by the sink alone, indicating that other, less well-understood, mechanisms are also at play. We believe that ILE also directly benefits cardiovascular function and have confirmed in preliminary experiments that the infusion of lipid emulsion in the intact rat exerts positive effecs on cardiac contractility and aortic blood flow. We hypothesize that this results in part from direc, positive effects of fatty acid metabolism on cardiac function. Moreover, it is well-established tha tissue ischemia can cause intercellular endothelial gaps to expand, thereby allowing liposomes to migrate into the myocardial interstitium. Such passive targeting of lipid particles, essentially nano-medicine, will bypass the normal tissue barriers to diffusion of drug away from cells and diminish the response time to lipid signal effectors. We hypothesize that extravascular migration of lipid particles contributes to the overall efficacy of ILE in reversing cardiac drug toxicity. W propose studies to test the metabolic effects of ILE and transendothelial migration of lipid particles. Finally, we seek to improve the translation of ILE to cocaine-related toxicity and longer-lasting overdoses such as calcium channel blocker toxicity. Improved patient safety and outcomes from drug toxicity are the over-arching goals of this project.

描述(由申请人提供)： 由PI以前的VA Merit奖资助的工作直接促成了一种新颖的、现在被广泛接受的局部麻醉剂全身毒性的挽救生命的治疗方法(LAST)。静脉注射脂肪乳剂(ILE)复苏也在许多情况下被用于快速逆转由广泛的脂溶性(脂溶)药物引起的急性心脏和神经毒性症状。在许多已发表的涉及上次或其他过量用药的病例报告中，即使在标准的复苏措施失败后，ILE仍然有效。ILE现在是美国区域麻醉学会、大不列颠和爱尔兰麻醉师协会、复苏理事会(英国)发布的治疗指南中的主要元素，并被添加到最新的美国心脏协会ACLS治疗指南中。吸毒过量是美国2007年造成3.6万人死亡的第二大意外死亡原因，排在枪伤之前，仅次于机动车事故。此外，考虑到非法药物滥用的普遍存在，以及老年人口难以遵守处方药物的说明，退伍军人面临的风险尤其大。这些处方药是长效钙通道阻滞剂，如果过量服用，可能会致命。值得注意的是，ILE已有效地用于治疗对标准复苏措施高度抵抗的许多常见处方药(例如，β受体阻滞剂、三环抗抑郁剂或钙通道阻滞剂)的过量使用。确定ILE的确切机制(S)有望提高其疗效，并为一系列危及生命的毒性药物过量提供有效的非专利解毒剂治疗。然而，ILE的确切机制还不是很清楚。传统的解释包括将有害的毒素分解成新产生的脂血浆相，或“脂沉”。然而，即使是这种机制也没有在体内得到严格的测试。此外，我们观察到，ILE的关键方面不能仅用汇来解释，这表明其他不太了解的机制也在发挥作用。我们认为ILE还直接有益于心血管功能，并已在初步实验中证实，在正常大鼠体内注入脂肪乳剂对心脏收缩能力和主动脉血流量有积极作用。我们推测，这在一定程度上是由于脂肪酸代谢对心脏功能的积极影响。此外，众所周知，组织缺血可导致细胞间内皮细胞间隙扩大，从而允许脂质体迁移到心肌间质。这种对脂质颗粒的被动靶向，基本上 纳米药物，将绕过正常的组织屏障，使药物扩散远离细胞，并缩短对脂质信号效应器的反应时间。我们假设脂质颗粒在血管外的迁移有助于ILE逆转心脏药物毒性的总体疗效。我们建议进行研究，以测试ILE的代谢效应和脂质颗粒的跨内皮迁移。最后，我们寻求将ILE转化为可卡因相关毒性和更持久的过量，如钙通道阻滞剂毒性。改善患者的安全性和药物毒性的结果是该项目的首要目标。